In the vertebrate olfactory system production of new sensory neurons continues throughout adult life. In any continuously renewing tissue a "steady state" in total cell number is achieved by a balance between cell proliferation and cell death. This implies that: 1) the rate of cell proliferation is regulated, 2) the rate of cell death is regulated, and 3) the regulating factors for cell proliferation and cell death are linked. The overall aim of this proposal is to examine several aspects of cell proliferation and cell death in olfactory epithelium. Earlier experiments had shown that olfactory cell proliferation can be up-and down-regulated by experimental manipulations. Preliminary data implicate two growth factors, Epidermal Growth Factor (EGF) and Transforming Growth Factor-a (TGF-a), in up-regulation of cell proliferation in an in vitro assay. These are both members of what is called the EGF family of growth factors. The working hypothesis is that members of the EGF family of growth factors participate in the regulation of mitotic rate in olfactory epithelium. This proposal represents a multidisciplinary approach to the study of cellular dynamics in the olfactory sensory epithelium. One aim is to determine whether the EGF family of growth factors and their cognate receptors are functional participants in the regulation of olfactory (or supporting) cell proliferation both in vitro and in vivo. Another aim is to test other growth factors for their efficacy in enhancing proliferation in olfactory epithelium. Several techniques, including organ culture, immunohistochemistry, electron microscopy, in situ hybridization and biochemistry will be used in these experiments. The other aspect of how the olfactory cell population numbers are maintained is the regulation of cell death. Very little detailed information is available about the mechanism of cell death in the olfactory system. Part of this proposal is designed to obtain some baseline information; for example, electron microscope studies on cell death following ablation of the olfactory bulb will be done to acquire detailed information about the specific morphological changes that occur in dying cells and to determine the means for their disposal. The literature on cell death in other systems suggests that certain biochemical events are observable most of the time in cells that are programmed to die. Probes for the identification of cell death markers in other tissues will be used to specify the biochemical and histochemical markers for olfactory cell death. Finally growth factors will be infused into unilaterally bulbectomized rats by a micropumping apparatus to try to rescue olfactory cells that are destined to die.